Valproic acid is a carboxylic acid that has been used to treat epilepsy and other CNS disorders such as manic episodes in bipolar disorder and in migraine headaches. More recent research has shown it to be a strong histone deacetylase (HDAC) Class 1 epigenetic inhibitor. HDACs are chromatin remodeling factors that normally help condense DNA into its compact form. When chromatin is in its compacted form, transcription or other factors cannot access DNA and viruses that infect cells such as HIV stay bound and hidden, eluding the attack of anti-viral therapy. HDAC inhibitors including valproic acid are thought to transform the chromatin in the latently infected cell from its condensed (or transcriptional silent) form to its less condensed (or transcriptional active) form. HDAC inhibitors also have implications in stem cell proliferation and reprogramming of adult stem cells.
U.S. Pat. No. 5,162,573 describes 2-propyl-2-pentanoic acid (valproic acid) esters of formula (I):
and (E)-2-propyl-2-pentenoic acid (E)-2-valproenoic acid esters of formula (II)
wherein R is an alkoxyalkyl, alkanoyloxyalkyl, aroyloxyalkyl, alkoxycarbonyloxyalkyl, aralkenoyloxyalkyl group, a mono- or bicyclic heterocycloalkyl group, which may be saturated or unsaturated and optionally substituted with a C1-C4 alkyl group or an oxo group; the above cited alkyl, alkoxyl and alkanoyl groups having straight or branched chain and containing 1 to 10 carbon atoms.
In formulae I and II of U.S. Pat. No. 5,162,573, R preferably represents 2-methoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 1-methyl-2-methoxyethyl, acetoxymethyl, 2-acetoxyethyl, pivaloyloxymethyl, 1- and 2-pivaloyloxyethyl, 2-propyl-pentanoyloxymethyl, 2-propyl-pentenoyloxymethyl, 2-(2-propylpentanoyloxy)ethyl, 2-(2-propyl-pentenoyloxy)ethyl, 1-ethoxycarbonyloxyethyl, 2-benzoyloxyethyl, 2-(3,4,5-trimethoxylbenzoyloxy)ethyl, 2-cinnamoyloxyethyl, 2-phthalidyl, 2-(N-succinimido)ethyl, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl, 2-pyridylmethyl.
U.S. Pat. No. 7,579,375 discloses compounds of the formula
wherein R1 represents optionally protected hydroxy or oxo, indicates R-configuration, S-configuration or a mixture of these in an arbitrary proportion,n represents an integer of 1 to 3, andm represents 0 or an integer of 1 to 10; andwherein two or more R1's are not bound to the same carbon atom other than the terminal carbon atom,a salt thereof or a prodrug thereof. In some embodiments, the compound can have a metal.
U.S. Pat. No. 7,569,609 describes compounds of the formula (I):
wherein R1 is C1-10 alkyl having one carbon substituted by 1-3 of fluorine(s); R2 is hydroxy, C1-4 alkoxy, C1-4 alkoxy substituted by 1 of phenyl, or NR3R4, in which R3 and R4 each, independently, is (i) hydrogen, (ii) C1-4 alkyl, (iii) phenyl, (iv) phenyl substituted by C1-4 alkoxy or carboxyl, (v) 4-7 membered heterocyclic ring containing one nitrogen or (vi) C1-4 alkyl substituted by phenyl, phenyl substituted by C1-4 alkoxy or carboxyl, or 4-7 membered heterocyclic ring containing one nitrogen, or the nitrogen atom bonded to them, taken together is 4-7 membered saturated heterocyclic ring containing one or two nitrogen(s) or one nitrogen and one oxygen, or amino acid residue; with the proviso that, R1 is not F—(CH2)4—, F—(CH2)5—, F—(CH2)6—, F3C—CH2—; and non-toxic salts thereof and acid addition salts thereof,and compounds of formula (X):
wherein n is 0 or 1; R11 is hydrogen or chlorine; R5 is R7—CH2— or R8, or R5 and R11, taken together is C3-10 alkylidene; R7 is F—(CH2)m—, in which m is 4-6, F3C—CH2—, C2-10 alkyl substituted by 1 or 2 of chlorine(s), or C1-5 alkyl substituted by 1 or 2 of C1-4alkoxy, C3-7 cycloalkyl, phenyl or phenoxy; R8 is (i) C3-10 alkyl (ii) C3-10 alkenyl, (iii) C2-10 alkoxy, (iv) C2-10 alkylthio, (v) C3-7 cycloalkyl, (vi) phenyl or (vii) phenoxy; R6 is hydroxy, C1-4alkoxy, C1-4 alkoxy substituted by 1 of phenyl, or NR9R10, in which R9 and R16 each, independently, is (i) hydrogen, (ii) C1-4 alkyl, (iii) phenyl, (iv) phenyl substituted by C1-4 alkoxy or carboxyl, (v) 4-7 membered heterocyclic ring containing one nitrogen or (vi) C1-4 alkyl substituted by phenyl, phenyl substituted by C1-4alkoxy or carboxyl, or 4-7 membered heterocyclic ring containing one nitrogen, or the nitrogen atom bonded to them, taken together is 4-7 membered saturated heterocyclic ring containing one or two nitrogen(s) or one nitrogen and one oxygen, or amino acid residue; non-toxic salts thereof and acid addition salts thereof.
U.S. Pat. No. 5,672,746 describes compounds of formula
wherein R1 is —C≡CH, —CH═CH2, or —CH2—CH3,M is a hydrogen or a metal atom;R2 is independently a saturated, unsaturated with at least one double or triple bond, branched or unbranched C1-30 alkyl group, optionally substituted with an aliphatic or aromatic C3-9cyclohydrocarbon or heterocyclic group; with the proviso that when R1 is CH2—CH3, R2 is C5-30, and that formula I is not 2-n-propyl-4-pentynoic acid or 2-n-propyl-4-pentenoic acid (4-en-VPA).
Despite the potential utility of valproic acid and it analogs as an HDAC inhibitor, low solubility of the carboxylic acid compounds limit application of these compounds. Thus, there is still a need for the development of new valproic acid analogs that will allow the production of better formulations that can easily be administered to the patient.